Long-standing Type 1 Diabetes Research Articles

Effects of dapagliflozin in heart failure according to duration of type 2 diabetes: a patient-level meta-analysis of DAPA-HF and DELIVER

Abstract Introduction Type 2 diabetes (T2D) is a common comorbidity in heart failure (HF), and long-standing T2D is associated with worse outcomes. Purpose To investigate the efficacy and safety of dapagliflozin, compared with placebo, according to duration of T2D in patients with HF and established T2D. Methods We conducted a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the effects of dapagliflozin, compared with placebo, in patients with HF with reduced ejection fraction and HF with mildly reduced/preserved ejection fraction, respectively. T2D duration was categorized as <5 years, 6-10 years, and >11 years. The primary outcome was a composite of worsening HF or cardiovascular death. Results Of the 4,784 patients with a history of T2D, 1,879 (39.3%) had a T2D duration of <5 years, 1,074 (22.4%) 5-10 years, and 1,831 (38.3%) >11 years. Patients with longer-duration T2D were older, more often female, and White, and had a higher HbA1c, body mass index, and left ventricular ejection fraction. They were more likely to have ischaemic heart disease, peripheral artery disease, hypertension, and chronic kidney disease, but were less likely to have atrial fibrillation/flutter. Although patients with longer-duration T2D had longer duration of HF, they were not more likely to have a prior HF hospitalization or worse New York Heart Association functional class. Despite similar N-terminal pro-B-type natriuretic peptide levels, patients with longer-duration T2D had a higher risk of the primary outcome, even after adjustment for potential confounders (<5 years, reference; 6-10 years, HR 1.25 [95% CI, 1.06-1.46]; >11 years, HR 1.33 [1.15-1.54]). The benefit of dapagliflozin on the primary outcome was consistent across T2D duration category: <5 years, HR 0.85 (95% CI, 0.69-1.04); 5-10 years, HR 0.65 (0.51-0.83); >11 years, HR 0.84 (0.70-1.01) (Pinteraction=0.18). Dapagliflozin reduced the risk of secondary clinical outcomes and increased (improved) mean KCCQ scores from baseline to 8 months, regardless of T2D duration (Table). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of T2D duration. Conclusions Dapagliflozin reduced the risk of worsening HF or cardiovascular death, and improved symptoms, in patients with HF and T2D, irrespective of T2D duration.

6519 BCG Clinical Trial Programs in Advanced Type 1 Diabetes - 2024 Update

Abstract Disclosure: W.M. Kühtreiber: None. B. Thach: None. H. Hayashi: None. L. Adams: None. N. Hullavarad: None. D.A. Mounier: None. K. Le: None. E. Bulczynski: None. J.L. Dorsey: None. N. Kartsounis: None. J. Braley: None. H. Zheng: None. D.L. Faustman: None. The bacillus Calmette-Guerin (BCG) vaccine, originally developed a century ago to prevent tuberculosis infection, has today advanced in multiple clinical trials for the treatment of the type 1 diabetes (T1D), other forms of autoimmunity and infectious disease. At our institution, over 500 individuals with type 1 diabetes have been enrolled in ongoing BCG clinical protocols to test BCG’s ability to lower HbA1c, reduce insulin requirements and stabilize day-to-day fluctuations in blood sugars; 300 have been treated with BCG. In a completed randomized, placebo-controlled Phase I trial in adults with established T1D, long-term follow up continues to show that HbA1c values are durably lowered for 8+ years after multi-dose BCG treatment. In two open-label clinical trials in adults with juvenile-onset diabetes, a 10-15% reduction of HbA1c was observed after multi-dose BCG treatment. A randomized, double-blinded Phase II trial in adults with longstanding T1D has followed all patients in the BCG-treated (n=100) and placebo groups (n=50) for five years and is pending read-out. The primary outcome of all the trials is HbA1c lowering. Two new, randomized, double-blinded pediatric trials are testing the potential benefits of BCG vaccination with active enrollment ongoing. One is testing BCG in children ages 12 to 18 with more than 2 years since T1D diagnosis. The other is enrolling children ages 8 to 18 with less than 1 year since T1D diagnosis. BCG vaccine therapy may provide a safe and affordable medical intervention in individuals with longstanding T1D and works decades after disease onset by changing glucose metabolism within lymphocytes, independently of the pancreas. Presentation: 6/3/2024

Microvascular disease and early diabetes onset are associated with deficits in femoral neck bone density and structure among older adults with longstanding type 1 diabetes.

Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribute to hip fracture in T1D. In this retrospective cohort study, we identified 101 adults with T1D and 181 age-, sex-, and race-matched non-diabetic controls (CON) who received abdominal or pelvis CT exams from 2010 to 2020. Among adults with T1D, 33 (33%) had mild-to-moderate nephropathy, 61 (60%) had neuropathy, and 71 (70%) had retinopathy. Within the whole cohort, adults with T1D tended to have lower FN density, though differences did not reach statistical significance. The subset of the T1D group who were diagnosed before age 15 had lower total BMC (-14%, TtBMC), cortical BMC (-19.5%, CtBMC), and smaller Ct cross-sectional area (-12.6, CtCSA) than their matched controls (p<.05 for all). Individuals with T1D who were diagnosed at a later age did not differ from controls in any bone outcome (p>.21). Furthermore, adults with T1D and nephropathy had lower FN aBMD (-10.6%), TtBMC (-17%), CtBMC (-24%), and smaller CtCSA (-15.4%) compared to matched controls (p<.05 for all). Adults with T1D and neuropathy had cortical bone deficits (8.4%-12%, p<.04). In summary, among older adults with T1D, those who were diagnosed before the age of 15yr, as well as those with nephropathy and neuropathy had unfavorable bone outcomes at the FN, which may contribute to the high risk of hip fractures among patients with T1D. These novel observations highlight the longstanding detrimental impact of T1D when present during bone accrual and skeletal fragility as an additional complication of microvascular disease in individuals with T1D.

Etiologies underlying subtypes of long-standing type 2 diabetes.

Attempts to subtype, type 2 diabetes (T2D) have mostly focused on newly diagnosed European patients. In this study, our aim was to subtype T2D in a non-white Emirati ethnic population with long-standing disease, using unsupervised soft clustering, based on etiological determinants. The Auto Cluster model in the IBM SPSS Modeler was used to cluster data from 348 Emirati patients with long-standing T2D. Five predictor variables (fasting blood glucose (FBG), fasting serum insulin (FSI), body mass index (BMI), hemoglobin A1c (HbA1c) and age at diagnosis) were used to determine the appropriate number of clusters and their clinical characteristics. Multinomial logistic regression was used to validate clustering results. Five clusters were identified; the first four matched Ahlqvist et al subgroups: severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), and a fifth new subtype of mild early onset diabetes (MEOD). The Modeler algorithm allows for soft assignments, in which a data point can be assigned to multiple clusters with different probabilities. There were 151 patients (43%) with membership in cluster peaks with no overlap. The remaining 197 patients (57%) showed extensive overlap between clusters at the base of distributions. Despite the complex picture of long-standing T2D with comorbidities and complications, our study demonstrates the feasibility of identifying subtypes and their underlying causes. While clustering provides valuable insights into the architecture of T2D subtypes, its application to individual patient management would remain limited due to overlapping characteristics. Therefore, integrating simplified, personalized metabolic profiles with clustering holds greater promise for guiding clinical decisions than subtyping alone.

Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment

Lack of understanding of the pathophysiology of gastrointestinal (GI) complications in type 1 diabetes (T1D), including altered intestinal transcriptomes and protein expression represents a major gap in the management of these patients. Human enteroids have emerged as a physiologically relevant model of the intestinal epithelium but establishing enteroids from individuals with long-standing T1D has proven difficult. We successfully established duodenal enteroids using endoscopic biopsies from pediatric T1D patients and compared them with aged-matched enteroids from healthy subjects (HS) using bulk RNA sequencing (RNA-seq), and functional analyses of ion transport processes. RNA-seq analysis showed significant differences in genes and pathways associated with cell differentiation and proliferation, cell fate commitment, and brush border membrane. Further validation of these results showed higher expression of enteroendocrine cells, and the proliferating cell marker Ki-67, significantly lower expression of NHE3, lower epithelial barrier integrity, and higher fluid secretion in response to cAMP and elevated calcium in T1D enteroids. Enteroids established from pediatric T1D duodenum identify characteristics of an abnormal intestinal epithelium and are distinct from HS. Our data supports the use of pediatric enteroids as an ex-vivo model to advance studies of GI complications and drug discovery in T1D patients.

Erectile Dysfunction and Depression Prevalence Among Male Patients with Type II Diabetes.

Patients with Type 2 Diabetes (T2D) are at substantial risk for developing erectile dysfunction (ED). The primary goal of this study was to assess the prevalence of ED and depression among T2D patients and the associated risk factors. A cross-sectional study was conducted for adult T2D patients who had a routine clinic visit between January-August 2023. Structured questionnaires formed with two validated questionnaires - the International Index of Erectile Function short form (IIEF-5) and Patient Health Questionnaire (PHQ-9) - were used to screen for ED and depression, respectively. A total of 478 male patients with T2D with a mean age of 59.2 ± 10.8 years, mostly married, with long standing T2D were included. Hyperlipidemia followed by hypertension were the most reported comorbidities. Of the patients, 61.3% had reported no depression and were less likely to have ED or severe ED (p <0.001) and more likely to be physically active and to report no smoking (p <0.0001) when compared to those with depression. Fifty-two percent of the patients reported moderate and severe ED and those were older in age (p = 0.031), had longer duration of T2D diagnosis (p = 0.005), were more likely to have any comorbidities (p <0.05), were less likely to have a university degree and higher income (both p <0.001), were less likely to be on oral hypoglycemic agents (OHA) (p <0.001), had worse glycemic control parameters (p = 0.463), were more likely to have positive urine microalbuminuria (p = 0.019), and were less likely to be physically active (p = 0.048) when compared to patients with no or milder degree of ED. ED is highly prevalent in our study sample, with half of the patients having moderate to severe ED and being more likely to have depression. Older age, long-standing T2D, comorbidities, socioeconomic disadvantage, and sedentary lifestyle were all significantly associated with ED.

Epicardial and intra-thoracic adipose tissue and cardiovascular calcifications in type 1 diabetes (T1D) in epidemiology of diabetes Interventions and Complications (EDIC): A pilot study

ObjectiveCoronary artery, aortic valve, and descending aorta calcification (CAC, AVC, DAC) are manifestations of atherosclerosis, and cardiac epicardial adipose tissue (EAT) indicates heart adiposity. This study explored the association between cardiac adipose tissue and cardiovascular calcification in participants with long-standing T1D. MethodsEAT and intra-thoracic adipose tissue (IAT) were measured in 100 T1D subjects with cardiac computed tomography (CT) scans in the EDIC study. Volume analysis software was used to measure fat volumes. Spearman correlations were calculated between CAC, AVC, DAC with EAT, and IAT. Associations were evaluated using multiple linear and logistic regression models. ResultsParticipants ranged in age from 32 to 57. Mean EAT, and IAT were 38.5 and 50.8 mm3, respectively, and the prevalence of CAC, AVC, and DAC was 43.6 %, 4.7 %, and 26.8 %, respectively. CAC was positively correlated with age (p-value = 0.0001) and EAT (p-value = 0.0149) but not with AVC and DAC; IAT was not associated with calcified lesions. In models adjusted for age and sex, higher levels of EAT and IAT were associated with higher CAC (p-value < 0.0001 for both) and higher AVC (p-values of 0.0111 and 0.0053, respectively), but not with DAC. The associations with CAC remained significant (p-value < 0.0001) after further adjustment for smoking, systolic blood pressure, BMI, and LDL, while the associations with AVC did not remain significant. ConclusionIn participants with T1D, higher EAT and IAT levels are correlated with higher CAC scores. EAT and IAT were not independently correlated with DAC or AVC.

The Complex Network of Cytokines and Chemokines in Pediatric Patients with Long-Standing Type 1 Diabetes.

Type 1 diabetes (T1D) is a progressive disorder leading to the development of microangiopathies and macroangiopathies. Numerous cytokines and chemokines are involved in the pathogenesis of T1D complications. The study aimed to assess the presence of complications in patients with long-standing T1D and its relationship with serum biomarker concentrations. We examined 52 T1D subjects, with a disease duration ≥4 years and 39 healthy controls. The group of T1D patients was further divided into subgroups based on the duration of the disease (<7 years and ≥7 years) and the metabolic control assessed by the HbAlc level (<8% and ≥8%). We used Luminex Technology to assess a wide range of biomarker concentrations. A 24 h urine test was done to evaluate the rate of albuminuria. Optical coherence tomography (OCT) was conducted to detect early retinopathic changes. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (IMT). T1D patients showed remarkably higher concentrations of EGF, eotaxin/CCL11, MDC/CCL22, sCD40L, TGF-α, and TNF-α. Moreover, we reported statistically significant correlations between cytokines and IMT. Biomarker concentrations depend on numerous factors such as disease duration, metabolic control, and the presence of complications. Although the majority of pediatric T1D patients do not present signs of overt complications, it is indispensable to conduct the screening for angiopathies already in childhood, as its early recognition may attenuate the further progression of complications.

Barriers and Enablers to the Adoption of a Healthier Diet Using an App: Qualitative Interview Study With Patients With Type 2 Diabetes Mellitus.

Adopting a healthy diet is one of the cornerstones of type 2 diabetes (T2D) management. Apps are increasingly used in diabetes self-management, but most studies to date have focused on assessing their impact in terms of weight loss or glycemic control, with limited evidence on the behavioral factors that influence app use to change dietary habits. The main objectives of this study were to assess the enablers and barriers to adopting a healthier diet using the Gro Health app in 2 patient groups with T2D (patients with recently diagnosed and long-standing T2D) and to identify behavior change techniques (BCTs) to enhance enablers and overcome barriers. Two semistructured qualitative interview studies were conducted; the first study took place between June and July 2021, with a sample of 8 patients with recently diagnosed (<12 mo) T2D, whereas the second study was conducted between May and June 2022 and included 15 patients with long-standing (>18 mo) T2D. In both studies, topic guides were informed by the Capability, Opportunity, Motivation, and Behavior model and the Theoretical Domains Framework. Transcripts were analyzed using a combined deductive framework and inductive thematic analysis approach. The Behavior Change Wheel framework was applied to identify appropriate BCTs that could be used in future iterations of apps for patients with diabetes. Themes were compared between the patient groups. This study identified similarities and differences between patient groups in terms of enablers and barriers to adopting a healthier diet using the app. The main enablers for recently diagnosed patients included the acquired knowledge about T2D diets and skills to implement these, whereas the main barriers were the difficulty in deciding which app features to use and limited cooking skills. By contrast, for patients with long-standing T2D, the main enablers included knowledge validation provided by the app, along with app elements to help self-regulate food intake; the main barriers were the limited interest paid to the content provided or limited skills engaging with apps in general. Both groups reported more enablers than barriers to performing the target behavior when using the app. Consequently, BCTs were selected to address key barriers in both groups, such as simplifying the information hierarchy in the app interface, including tutorials demonstrating how to use the app features, and redesigning the landing page of the app to guide users toward these tutorials. Patients with recently diagnosed and long-standing T2D encountered similar enablers but slightly different barriers when using an app to adopting a healthier diet. Consequently, the development of app-based approaches to adopt a healthier diet should account for these similarities and differences within patient segments to reduce barriers to performing the target behavior.

Fasted C-Peptide Distribution and Associated Clinical Factors in Adults With Longstanding Type 1 Diabetes: Analysis of the Canadian Study of Longevity in Type 1 Diabetes

ObjectiveAlthough insulin production is reportedly retained in many people with longstanding type 1 diabetes (T1D), the magnitude and relevance of connecting peptide (C-peptide) production are uncertain. In this study, we aimed to define fasted C-peptide distributions and associated clinical factors. MethodsIn a cross-sectional analysis of the Canadian Study of Longevity, fasted serum and urinary C-peptide was measured in 74 patients with longstanding T1D (duration ≥50 years) and 75 age- and sex-matched controls. Extensive phenotyping for complications was performed and patient-reported variables were included. C-peptide distributions were analyzed, and multivariable logistic regression was used to assess the variable association in participants with T1D. ResultsThe 74 participants with T1D had a mean age of 66±8 years, a disease duration of 54 (interquartile range 52 to 58) years, and a glycated hemoglobin (A1C) of 7.4%±0.8% (56.8±9.15 mmol/mol). The 75 controls had a mean age of 65±8 years and an A1C of 5.7%±0.4% (38.4±4.05 mmol/mol). Participants with T1D had lower fasted serum C-peptide than controls (0.013±0.022 vs 1.595±1.099 nmol/L, p<0.001). Of the participants with T1D, C-peptide was detectable in 30 of 73 (41%) serum samples, 32 of 74 (43%) urine samples, and 48 of 74 (65%) for either serum or urine. The variables independently associated with detectable serum or urinary C-peptide were lower total daily insulin requirement (odds ratio 2.351 [for 1 lower unit/kg], p=0.013) and lower hypoglycemia worry score (odds ratio 1.059 [for 1 point lower on the worry subscore of the Hypoglycemia Fear Survey], p=0.030). ConclusionsAlthough detectable C-peptide in longstanding diabetes was common, the magnitude of concentration was extremely low when compared with age- and sex-matched controls. Despite minimal detectability, its presence is validated by lower insulin requirements and strongly associated with lower hypoglycemia worry.

Bone Structure and Turnover in Postmenopausal Women With Long-Standing Type 1 Diabetes.

Compromised bone structural and mechanical properties are implicated in the increased fracture risk in type 1 diabetes (T1D). We investigated bone structure and turnover by histomorphometry in postmenopausal women with T1D and controls without diabetes using tetracycline double-labeled transiliac bone biopsy. After in vivo tetracycline double labeling, postmenopausal women with T1D of at least 10 years and without diabetes underwent transiliac bone biopsy. An expert blinded to the study group performed histomorphometry. Static and dynamic histomorphometry measurements were performed and compared between the two groups. The analysis included 9 postmenopausal women with T1D (mean age 58.4 ± 7.1 years with 37.9 ± 10.9 years of diabetes and HbA1c 7.1% ± 0.4%) and 7 postmenopausal women without diabetes (mean age 60.9 ± 3.3 years and HbA1c 5.4% ± 0.2%). There were no significant differences in serum PTH (38.6 ± 8.1 versus 51.9 ± 23.9 pg/mL), CTX (0.4 ± 0.2 versus 0.51 ± 0.34 ng/mL), or P1NP (64.5 ± 26.2 versus 87.3 ± 45.3 ng/mL). Serum 25-hydroxyvitamin D levels were higher in T1D than in controls (53.1 ± 20.8 versus 30.9 ± 8.2 ng/mL, p < 0.05). Bone structure metrics (bone volume, trabecular thickness, trabecular number, and cortical thickness) were similar between the groups. Indices of bone formation (osteoid volume, osteoid surface, and bone formation rate) were 40% lower in T1D and associated with lower activation frequency. However, the differences in bone formation were not statistically significant. Long-standing T1D may affect bone turnover, mainly bone formation, without significantly affecting bone structure. Further research is needed to understand bone turnover and factors affecting bone turnover in people with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

THU336 Correlation Between Dietary Advanced Glycation End-products (Ages) And Skin Ages In Adults With Longstanding T1D

Abstract Disclosure: A.B. Murthy: None. B.E. Gray: None. M. Cote: None. B. Zahedi: None. E.W. Yu: Grant Recipient; Self; Amgen Inc. Background: Advanced glycation end products (AGEs) are involved in the pathophysiology of diabetic complications, and are thought to accrue with aging, hyperglycemia, and through diet. Despite the postulated impact of dietary intake on circulating AGE levels, there is currently no validated methodology for dietary AGE (dAGE) assessment. Thus, we sought to develop a crosswalk algorithm to calculate AGE intake from the commonly utilized Block Food Frequency Questionnaire (FFQ), and to validate our algorithm by correlating dAGE to skin AGE values within a cohort of adults with Type 1 Diabetes (T1D). Methods: We performed preliminary analysis of 50 study participants from the ongoing Type 1 Diabetes Bone Health Connection (T1D BEACON) study evaluating postmenopausal women and men older than 50 years with T1D. Dietary AGE intake was quantified using a novel algorithm we developed to associate items from the 2014 Block FFQ with their AGE content as determined by ELISA in a published data set (Urribarri, et al. 2014). Mean daily dAGE intake (kU/day) was correlated with autoflourescent skin AGE values (AGE Reader, DiagnOptics Technologies) using multivariate linear regression, after adjusting for age and gender. Diabetic characteristics and complications were assessed through questionnaires, physical exams (mTCNS, DPNCheck), chart review, and urine/serum tests. Results: The average age of the T1D cohort was 62.7 ± 6.8 years, 50% were female, the average duration of diabetes was 45 ± 9.4 years, with average A1c of 7.2 ± 1.1. Regarding diabetic complications, 70% had retinopathy, 30% had microalbuminuria (urine albumin-creatinine ratio &amp;gt; 30 mcg/mg), and 33% had neuropathy (mTCNS score &amp;gt; 5). Using our novel algorithm, the mean daily dAGE intake was calculated as 13178 ± 4455 kU/day. Mean daily dAGE intake was significantly higher for men (15279 ± 6337 kU/day) compared to women (11628 ± 3699 kU/day) (p = 0.016). Importantly, dAGEs were significantly correlated with skin AGEs (r = 0.409, p = 0.004), an association that persisted after adjusting for age and gender (p = 0.005). Additionally, dAGEs were correlated with current A1c values (r=0.37, p = 0.009, adj. p = 0.042) and with BMI (r = 0.32, p = 0.024, adj. p = 0.020), even after adjusting for age and gender. No associations were found between dAGEs and retinopathy, microalbuminuria, or neuropathy. Additional analysis of the full planned cohort is ongoing, along with assessments of serum AGE levels. Conclusion: We have developed and validated a novel dietary AGE algorithm that quantifies dAGE intake using the Block FFQ and is correlated with skin AGEs and glycemic control among adults with T1D. If further validated in larger cohorts, we hope this dAGE tool will facilitate future investigation of the impact of dietary AGEs on diabetic complications. Presentation: Thursday, June 15, 2023

THU266 Lowered HbA1c In Individuals With Long-term Type 1 Diabetes Undergoing BCG Bladder Cancer Therapy

Abstract Disclosure: H. Dias: None. W. Kühtreiber: None. D.L. Faustman: None. Originally developed for the prevention of tuberculosis, the bacillus Calmette-Guérin (BCG) vaccine has shown benefit in diverse human diseases, including infection resistance, allergies, multiple sclerosis and autoimmune diabetes. BCG has also been approved in the United States and Europe since 1972 for early-stage bladder cancer, where it is administered commonly as 6 doses via intravesical therapy for 6 weeks (“high-dose intravesical BCG”). We analyzed three large databases-the Management Science Associates database (with Quest Diagnostics data) (N=263 million adults), the Research Patient Data Registry (RPDR) from the Massachusetts General Brigham (MGB) system (N=6.5 million), and data from Optum Labs (OL)(N=45 million) -for a correlation between high-dose intravesical BCG and HbA1c levels in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D). We identified subjects with documented T1D (N=19) or T2D (N=106) undergoing BCG therapy for bladder cancer, and then retrospectively assessed BCG’s subsequent year-by-year impact on blood sugar trends. T1D records were identified by searching for T1D diagnosis and insulin usage; records showing any history of oral hypoglycemic agents (e.g., metformin) were excluded. T2D records were searched for using T2D diagnosis and exclusion of any T1D diagnosis. No patients had a history of BCG treatment/vaccination other than for bladder cancer. Patients with T1D in the datasets showed downward trends in HbA1c values after high-dose intravesical BCG, but not patients with T2D. The data suggests that high-dose intravesical BCG therapy may contribute towards a drop in HbA1c values in T1D, but not T2D. This is consistent with earlier interventional trials of the BCG vaccine in longstanding T1D. Presentation: Thursday, June 15, 2023

Investigating immune profile by CyTOF in individuals with long-standing type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Eosinophils are found in pancreatic tissue from individuals with T1D. Eosinophilic suppression of T cells is dependent of the protein galectin-10. Little is known when it comes to the role of eosinophil granulocytes in type 1 diabetes. Here we show that individuals with long-standing T1D had lower levels of galectin-10hi eosinophils and a subgroup of galectin-10hi eosinophils were entirely absent in all T1D patients. In addition, 7% immature eosinophils were present in the circulation of T1D patients whereas 0.8% in healthy individuals. Furthermore, higher levels of CD4+CD8+ T cells and Th17 cells were observed in patients with T1D. Blood samples from 12 adult individuals with long-standing T1D and 12 healthy individuals were compared using cytometry by time-of-flight. Lower levels of galectin-10hi eosinophils, which are potent T cell suppressors, in individuals with T1D could indicate that activated T cells are enabled to unrestrictedly kill the insulin producing beta cells. This is the first study showing absence of galectin-10hi eosinophilic subgroup in individuals with T1D compared with healthy controls. This study is a first important step toward unraveling the role of the eosinophils in patients with T1D.

Disease Duration and Chronic Complications Associate With Immune Activation in Individuals With Longstanding Type 1 Diabetes.

Type 1 diabetes (T1D) is associated with alterations of the immune response which persist even after the autoimmunity aspect is resolved. Clinical factors that cause dysregulation, however, are not fully understood. To identify clinical factors that affect immune dysregulation in people with longstanding T1D. In this cross-sectional study, 243 participants with longstanding T1D were recruited between February 2016 and June 2017 at the Radboudumc, the Netherlands. Blood was drawn to determine immune cell phenotype and functionality, as well as circulating inflammatory proteome. Multivariate linear regression was used to determine the association between glycated hemoglobin (HbA1c) levels, duration of diabetes, insulin need, and diabetes complications with inflammation. HbA1c level is positively associated with circulating inflammatory markers (P < .05), but not with immune cell number and phenotype. Diabetes duration is associated with increased number of circulating immune cells (P < .05), inflammatory proteome (P < .05), and negatively associated with adaptive immune response against Mycobacterium tuberculosis and Rhizopus oryzae (P < .05). Diabetes nephropathy is associated with increased circulating immune cells (P < .05) and inflammatory markers (P < .05). Disease duration and chronic complications associate with persistent alterations in the immune response of individuals with long standing T1D.

Defining and Phenotyping Gastric Abnormalities in Long-Term Type 1 Diabetes Using a Novel Body Surface Gastric Mapping Device

Diabetic gastroenteropathy is associated with poor glycemic control and morbidity in people with type 1 diabetes (T1D). There is a lack of noninvasive techniques to assess and monitor gastric abnormalities. We aimed to define phenotypes of gastric myoelectrical abnormalities in people with longstanding T1D with and without symptoms using a novel noninvasive body surface gastric mapping (BSGM) device. BSGM was performed on people with T1D of >10 years duration and matched controls, employing Gastric Alimetry (Alimetry, New Zealand), comprising of a high-resolution 64-channel array, validated symptom-logging App, and wearable reader. Thirty-two people with T1D were recruited (15 with a high symptom burden), and 32 controls. Those with symptoms showed more unstable gastric myoelectrical activity (Gastric Alimetry Rhythm Index 0.39 vs 0.51, P= .017; and lower average spatial covariance 0.48 vs 0.51, P= .009) compared with controls. Symptomatic patients also had a higher prevalence of peripheral neuropathy (67% vs 6%, P= .001), anxiety/depression diagnoses (27% vs 0%, P= .001), and higher mean hemoglobin A1C levels (76 vs 56 mmol/mol, P < .001). BSGM defined distinct phenotypes in T1D participants including those with markedly unstable gastric rhythms (4/32, 12.5%) and abnormally high gastric frequencies (9/32, 28%). Deviation in gastric frequency was positively correlated with symptoms of bloating, upper gut pain, nausea and vomiting, and fullness (R > 0.35, P < .05). Gastric symptoms in people with longstanding T1D correlate with myoelectrical abnormalities on BSGM evaluation, in addition to glycemic control, psychological comorbidities, and peripheral neuropathy. BSGM using Gastric Alimetry identified a range of myoelectrical phenotypes, presenting targets for diagnosis, monitoring, and therapy.

Other specific types of diabetes and exocrine pancreatic insufficiency (update2023)

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down‑, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type1 and long-standing type2 diabetes.

Associations of Dietary Intake with the Intestinal Microbiota and Short-Chain Fatty Acids Among Young Adults with Type 1 Diabetes and Overweight or Obesity

BackgroundDiet, a key component of type 1 diabetes (T1D) management, modulates the intestinal microbiota and its metabolically active byproducts—including SCFA—through fermentation of dietary carbohydrates such as fiber. However, the diet–microbiome relationship remains largely unexplored in longstanding T1D. ObjectivesWe evaluated whether increased carbohydrate intake, including fiber, is associated with increased SCFA-producing gut microbes, SCFA, and intestinal microbial diversity among young adults with longstanding T1D and overweight or obesity. MethodsYoung adult men and women with T1D for ≥1 y, aged 19–30 y, and BMI of 27.0–39.9 kg/m2 at baseline provided stool samples at baseline and 3, 6, and 9 mo of a randomized dietary weight loss trial. Diet was assessed by 1–2 24-h recalls. The abundance of SCFA-producing microbes was measured using 16S rRNA gene sequencing. GC-MS measured fecal SCFA (acetate, butyrate, propionate, and total) concentrations. Adjusted and Bonferroni-corrected generalized estimating equations modeled associations of dietary fiber (total, soluble, and pectins) and carbohydrate (available carbohydrate, and fructose) with microbiome-related outcomes. Primary analyses were restricted to data collected before COVID-19 interruptions. ResultsFiber (total and soluble) and carbohydrates (available and fructose) were positively associated with total SCFA and acetate concentrations (n = 40 participants, 52 visits). Each 10 g/d of total and soluble fiber intake was associated with an additional 8.8 μmol/g (95% CI: 4.5, 12.8 μmol/g; P = 0.006) and 24.0 μmol/g (95% CI: 12.9, 35.1 μmol/g; P = 0.003) of fecal acetate, respectively. Available carbohydrate intake was positively associated with SCFA producers Roseburia and Ruminococcus gnavus. All diet variables except pectin were inversely associated with normalized abundance of Bacteroides and Alistipes. Fructose was inversely associated with Akkermansia abundance. ConclusionsIn young adults with longstanding T1D, fiber and carbohydrate intake were associated positively with fecal SCFA but had variable associations with SCFA-producing gut microbes. Controlled feeding studies should determine whether gut microbes and SCFA can be directly manipulated in T1D.

Pregnancy induces pancreatic insulin secretion in women with long-standing type 1 diabetes

IntroductionPregnancy entails both pancreatic adaptations with increasing β-cell mass and immunological alterations in healthy women. In this study, we have examined the effects of pregnancy on β-cell function and immunological...

Predictors of change in hypoglycemia unawareness among patients with type 1 diabetes.

To analyse predictors of hypoglycemia unawareness (HU) and improvement in Clarke score in clinical practice. We retrospectively identified patients with type 1 diabetes (T1D) at an academic T1D clinic who completed HU surveys 6-12months apart. HU (Clarke score ≥4) and improvement in Clarke score (decrease by ≥1 point or more clinically relevant ≥2 point) were assessed in univariable relationships and using multivariable logistic regression. Of the 300 participants, median diabetes duration was 19years, 47 had HU at baseline, and 91 had an improvement by 1 point while 21 had an improvement by 2 points. Patients with baseline Clarke score ≥4 who had ≥1 or ≥2 point improvement had lower filtration rate (eGFR) than those who did not. After adjustment for other variables, gender (male OR 0.33, 95% CI 0.15, 0.74), log diabetes duration (OR 6.40, 95% CI 2.84, 14.5), and eGFR <60ml/min/1.73m2 (5.56, 95% CI 1.98, 15.6) were independent predictors of baseline HU. Continuous glucose monitoring use (OR 2.04, 95% CI 1.20, 3.48) and log diabetes duration (OR 1.78, 95% CI 1.22, 2.60) were independent predictors of 1 point improvement and eGFR <60ml/min/1.73m2 (OR 10.5, 95% CI 3.64, 30.0) and an education visit (OR 2.64, 95% CI 1.01, 6.89) were independent predictors of 2 point improvement in Clarke score. Diabetes duration, gender, and eGFR were independent predictors of HU. Improvement in Clarke score is possible in patients with long-standing T1D, underscoring the need for additional study.